The overall objective of this research is to characterize the effects of metabolic, pharmacologic, and mechanical stimuli on the activity and role of left ventricular & atrial receptors with vagal C-fiber afferents. The proposal has three major areas: I. Effects of pH, pO2, pCO2, drugs, and naturally occurring substances on left atrial and ventricular receptors with nonmyelinated vagal afferents will be studied in asystolic or fibrillating hearts during retrograde coronary perfusion with oxygenated Krebs solution. The goal is to determine the primary effects of these interventions on receptors independent of secondary effects mediated through myocardial changes. The response of the receptor in the resting state and during a constant stimulus (static or pulsatile balloon distention) will be measured during control, experimental (e.g. drug administration), and recovery period. O2 consumption and coronary flow will be measured to assure that receptor responses do not result from myocardial and coronary vascular responses. II. Investigation of the determinants of activation and frequency of discharge of left ventricular mechanoreceptors with vagal C-fiber afferents will be performed in isolated beating hearts during coronary perfusion with oxygenated Krebs solution. The ventricle will be volume loaded with a balloon with transient or sustained distentions at different phases of the cardiac cycle. The receptor's location, depth in the myocardium, the behavior of the ventricle in the receptor region, and the receptor response to volume and inotropic stimuli will be studied to establish the mechanisms of activation and the determinants of discharge frequency. III. The effect of digitalis on tonic inhibition of the vasomotor center by cardiopulmonary receptors will be studied in anesthetized dogs. With aortic nerves cut and carotid sinuses either denervated or perfused at constant pressure, the response to reversible vagal interruption (cold block) will be measured before and after administration of digitalis.